Unveiling Novel KRAS G12V Inhibitors: A Comprehensive Study Using Computer-aided Drug Design Approach
Amena Khatun Manica
Department of Chemistry, University of New Haven, Connecticut, USA.
Benedicta Quainoo
Department of Chemistry and Biochemistry, Texas Tech University, Texas, USA.
Jonathan Cudjoe
Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
Aminat Motunrayo Adekunle
Department of Biochemistry, University of Lagos, Lagos, Nigeria.
Cyril Agadagba
Department of Chemistry and Biochemistry, Baylor University, Waco, Texas, USA.
Temilade Rukayat Adeniran
Department of Chemistry and Biochemistry, Baylor University, Waco, Texas, USA.
Oluwatosin Oluwafunmilola Oluwafemi
Department of Population Health & Leadership, Public Health Program, University of New Haven, CT, USA.
Ayomide Daniel Oluwafemi
Department of Chemistry, Western Washington University, Washington, USA.
Abasiodiong Ekanem
Department of Population Health & Leadership, Public Health Program, University of New Haven, CT, USA.
Hikmat Opeyemi Sulaiman
Department of Pharmaceutical and Medicinal Chemistry, University of Ilorin, Ilorin, Kwara State, Nigeria.
Farimah Mohammadi
Department of Biochemistry, University of Tennessee, Tennessee, USA.
Emmanuel Parkay Oladokun
School of Biological Sciences, Illinois State University, Illinois, USA.
Mariam Omowunmi Oguntunji
Biochemistry Unit and Nutrition, Department of Chemical Sciences, Fountain University Osogbo, Osun State, Nigeria.
Roheemah Olamide Oni *
Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Oyo State, Nigeria.
*Author to whom correspondence should be addressed.
Abstract
The KRAS G12V mutation is a formidable oncogenic driver implicated in the pathogenesis of several aggressive cancers, including pancreatic ductal adenocarcinoma, non-small cell lung cancer, and colorectal cancer. Overcoming the historical challenges associated with targeting KRAS mutations, this study harnesses advanced computer-aided drug design (CADD) techniques to unearth novel and potent inhibitors. By leveraging the structural paradigms of clinically validated KRAS inhibitors sotorasib and adagrasib, we systematically screened the PubChem database, yielding 628 promising candidates. Molecular docking simulations pinpointed three standout compounds: CID_138637935, CID_155344829, and CID_165158764, distinguished by their exceptional binding affinities. Subsequent molecular dynamics (MD) simulations offered an in-depth exploration of these compounds, revealing CID_155344829 as the frontrunner, with unparalleled stability, and compact structural integrity. While CID_138637935 and CID_165158764 displayed notable potential, further refinement is warranted. Our findings illuminate the transformative potential of CADD in revolutionizing cancer therapeutics and lay the groundwork for future in vitro and in vivo investigations to validate and optimize these novel KRAS G12V inhibitors.
Keywords: KRAS G12V, computer-aided drug design, molecular dynamics simulation, cancer therapeutics, virtual screening